The present invention relates to a class of pyrazine compounds which are useful in the treatment of central nervous system (CNS) diseases and disorders and to their pharmaceutically acceptable derivatives, to pharmaceutical compositions containing them, to their use in the treatment of such disorders and to methods of preparation.
Numerous phenyl pyrazine derivatives are known in the prior art. For example, Synthesis (1987, (10), 914-915, describes phenyl pyrazine derivatives including, inter alia, 3-(4-chlorophenyl)pyrazinamine. No pharmaceutical utility is however described in that prior art document.
The present invention relates to pyrazine derivatives which are sodium channel blockers. The compounds are surprisingly potent anti-convulsants having increased potency with respect to lamotrigine and increased selectivity in terms of CNS side-effects and inhibition of the enzyme dihydrofolate reductase. The compounds are therefore useful in the treatment of CNS diseases such as epilepsy.
Accordingly, the present invention provides a compound of formula (I) 
wherein
R1 is phenyl substituted by one or more halogen atoms;
R2 is xe2x80x94NH2;
R3 is xe2x80x94NH2 or hydrogen;
R4 is xe2x80x94CXNRaRb, xe2x80x94CXNHxe2x80x94(CH2)yxe2x80x94NRaRb;
xe2x80x83wherein
X is xe2x95x90O or xe2x95x90S;
y is an integer zero, 1 or 2;
Ra and Rb, which may be the same or different, are selected from hydrogen and C1-4 alkyl, or together with the nitrogen atom to which they are attached, form a saturated 5- or 6-membered heterocycle containing one or two nitrogen heteroatoms, which heterocycle can be further substituted with one or more C,4 alkyl groups;
and pharmaceutically acceptable derivatives thereof.
By pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt, solvate or ester, or salt or solvate of such ester of the compounds of formula (I), or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof (eg. a prodrug).
It will be appreciated that, for pharmaceutical use, the salts referred to above will be the physiologically acceptable salts, but other salts may find use, for example in the preparation of compounds of formula (I) and the physiologically acceptable salts thereof.
Suitable pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts formed with inorganic or organic acids, preferably inorganic acids, e.g. hydrochlorides, hydrobromides and sulphates.
Suitable prodrugs are well-known in the art and include N-acyl derivatives, for example at any of the nitrogens in the compounds of formula (I), for example simple acyl derivatives such as acetyl, propionyl and the like or groups such as Rxe2x80x94Oxe2x80x94CH2-nitrogen or Rxe2x80x94Oxe2x80x94C(O)-nitrogen.
As used herein, the term halogen atom includes fluorine, chlorine, bromine or iodine.
The term C1-4alkyl as used herein includes straight chained and branched alkyl groups containing 1 to 4 carbon atoms, and in particular includes methyl and isopropyl.
The term saturated 5- or 6-membered heterocycle containing one or two nitrogen heteroatoms as used herein includes 5- or 6-membered heterocycles containing at least one nitrogen heteroatom, and preferably two nitrogen heteroatoms, which heterocycle can be further substituted with one or more C1-4 alkyl groups. A particularly suitable heterocycle is a pyrrolidine or a piperazine ring.
R1 is aptly selected from phenyl substituted by one or more halogen atoms. Particularly, R1 represents phenyl substituted by more than 1 halogen atom, such as di- or tri-halogenated phenyl. Preferably, the halogen atoms are all identical. Preferably, the halogen substituents in R1 are chloro. Suitably R1 is selected from 2,3,5-trichlorophenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl. Preferably, R1 is 2,3,5-trichlorophenyl.
R3 is preferably xe2x80x94NH2.
When R4 is the group xe2x80x94CXNRaRb or xe2x80x94CXNHxe2x80x94(CH2)yxe2x80x94NRaRb where Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated 5- or 6-membered heterocycle containing one or two nitrogen heteroatoms atoms, this saturated 5- or 6-membered heterocycle is suitably a pyrrolidine or piperazine ring.
X is preferably xe2x95x90O.
The integer y is preferably 2.
When R4 is the group xe2x80x94CXNHxe2x80x94(CH2)yxe2x80x94NRaRb, Ra and Rb are preferably C1-4 alkyl. Preferred values for xe2x80x94CXNH(CH2)yNRaRb include for example xe2x80x94CONHxe2x80x94(CH2)2xe2x80x94N(CH3)2.
R4 is preferably the group xe2x80x94CXNRaRb. Preferably X is xe2x95x90O and, further preferred, are compounds where Ra and Rb are selected from hydrogen and C1-4 alkyl. Preferably R4 is xe2x80x94CONH2, xe2x80x94CONH(CH3), xe2x80x94CONH(CH2CH3), xe2x80x94CONH[CH(CH3)2] or xe2x80x94CON(CH3)2. A particularly preferred R4 is xe2x80x94CONH2.
It is to be understood that the present invention encompasses all isomers of the compounds of formula (I) and their pharmaceutically acceptable derivatives, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures).
Preferred compounds of the present invention include:
5-Carboxamido-2,6-diamino-3-(2,3,5-trichlorophenyl)pyrazine
2,6-Diamino-5-N-methylcarboxamido-3-(2,3,5-trichlorophenyl)pyrazine
2,6-Diamino-5-N-ethylcarboxamido-3-(2,3,5-trichlorophenyl )pyrazine
2,6-Diamino-5-N-isopropylcarboxamido-3-(2,3,5-trichlorophenyl)pyrazine
2,6-Diamino-5-N,N-dimethylcarboxamido-3-(2,3,5-trichlorophenyl)pyrazine
2,6-Diamino-5-thiocarboxamido-3-(2,3,5-trichlorophenyl)pyrazine
and pharmaceutically acceptable derivatives thereof.
A particularly preferred compound according to the invention is:
5-Carboxamido-2,6-diamino-3-(2,3,5-trichlorophenyl)pyrazine
and pharmaceutically acceptable derivatives thereof.
It is to be understood that the present invention covers all combinations of particular and preferred groups as described herein above.
The compounds of formula (I) are particularly useful as anticonvulsants. They are therefore useful in treating epilepsy. They may be used to improve the condition of a host, typically a human being, suffering from epilepsy. They may be employed to alleviate the symptoms of epilepsy in a host. xe2x80x9cEpilepsyxe2x80x9d is intended to include the following seizures:- simple partial seizures, complex partial seizures, secondary generalised seizures, generalised seizures including absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic clonic seizures and atonic seizures.
The compounds of formula (I) are additionally useful in the treatment of bipolar disorder, alternatively known as manic depression. Type I or II bipolar disorder may be treated. The compounds of formula (I) may thus be used to improve the condition of a human patient suffering from bipolar disorder. They may be used to alleviate the symptoms of bipolar disorder in a host. The compounds of formula (I) may also be used in the treatment of unipolar depression.
The compounds of formula (I) are also useful as analgesics. They are therefore useful in treating or preventing pain. They may be used to improve the condition of a host, typically a human being, suffering from pain. They may be employed to alleviate pain in a host. Thus, the compounds of formula (I) may be used as a pre-emptive analgesic to treat acute pain such as musculoskeletal pain, post operative pain and surgical pain, chronic pain such as chronic inflammatory pain (e.g. rheumatoid arthritis and osteoarthritis), neuropathic pain (e.g. post herpetic neuralgia, trigeminal neuralgia and sympathetically maintained pain) and pain associated with cancer and fibromyalgia. The compounds of formula (I) may also be used in the treatment or prevention of pain associated with migraine.
The compounds of formula (I) are further useful in the treatment of functional bowel disorders which include non-ulcer dyspepsia, non-cardiac chest pain and in particular irritable bowel syndrome. Irritable bowel syndrome is a gastrointestinal disorder characterised by the presence of abdominal pain and altered bowel habits without any evidence of organic disease. The compounds of formula (I) may thus be used to alleviate pain associated with irritable bowel syndrome. The condition of a human patient suffering from irritable bowel syndrome may thus be improved.
The compounds of formula (I) may also be useful in the treatment of neurodegenerative diseases, such as Alzheimer""s disease, ALS, motor neuron disease, Parkinson""s disease, macular degeneration and glaucoma. The compounds of formula (I) may also be useful in neuroprotection and in the treatment of neurodegeneration following stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinal cord injury or the like.
The compounds of formula (I) are further useful in the treatment of tinnitus.
Still further, the compounds of formula (I) are also useful in preventing or reducing dependence on, or preventing or reducing tolerance or reverse tolerance to, a dependence-inducing agent. Examples of dependence inducing agents include opioids (eg morphine), CNS depressants (eg ethanol), psychostimulants (eg cocaine) and nicotine.
According to a further aspect of the invention, we provide a compound of formula (I) or a pharmaceutically acceptable derivative thereof for use in human or veterinary medicine.
According to another aspect of the invention, we provide use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for use in the treatment of a disorder substantially as hereinbefore described.
According to a further aspect of the invention, we provide a method of treating a human or animal subject suffering from, or susceptible to, a disorder substantially as hereinbefore described, which method comprises administering to said subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof.
It is to be understood that reference to treatment as used herein includes treatment of established symptoms and prophylactic treatment, unless explicitly stated otherwise.
The compound of formula (I) and its salts may be administered orally at a dose of from 0.1 to 10 mg/kg body weight per day and more particularly 0.3 to 3 mg/kg body weight per day, calculated as the free base. The dose range for adult human beings is generally from 8 to 1000 mg/day, such as from 35 to 800 mg/day, preferably 20 to 200 mg/day, calculated as the free base.
The precise amount of the compounds of formula (I) administered to a host, particularly a human patient, will be the responsibility of the attendant physician.
However, the dose employed will depend upon a number of factors including the age and sex of the patient, the precise condition being treated and its severity, and the route of administration.
The compounds of formula (I) and their pharmaceutically acceptable derivatives are conveniently administered in the form of pharmaceutical compositions. Thus, in another aspect of the invention, we provide a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof adapted for use in human or veterinary medicine. Such compositions may conveniently be presented for use in conventional manner in admixture with one or more physiologically acceptable carriers or excipients.
While it is possible for the compounds of formula (I) or a pharmaceutically acceptable derivative thereof to be administered as the raw chemical, it is preferable to present it as a pharmaceutical formulation. The formulations of the present invention comprise the compounds of formula (I) or a pharmaceutically acceptable derivative thereof together with one or more acceptable carriers or diluents therefor and optionally other therapeutic ingredients. The carrier(s) must be xe2x80x9cacceptablexe2x80x9d in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The formulations include those suitable for oral, parenteral (including subcutaneous e.g. by injection or by depot tablet, intradermal, intrathecal, intramuscular e.g. by depot and intravenous), rectal and topical (including dermal, buccal and sublingual) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof (xe2x80x9cactive ingredientxe2x80x9d) with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets (e.g. chewable tablets in particular for paediatric administration) each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of a sterile liquid carrier, for example, water-for-injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter, hard fat or polyethylene glycol.
Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
The compounds of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
In addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
The compounds of formula (I) may be used in combination with other therapeutic agents, for example other anticonvulsants. When compounds of formula (I) or pharmaceutically acceptable derivatives thereof are used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route. The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof with a further therapeutic agent.
The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
When a compound of formula (I) or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same disease, the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
Preferred unit dosage formulations are those containing an effective daily dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient. Conveniently that may be from 5 mg to 1000 mg, such as from 8 mg to 1000 mg, more conveniently 35 mg to 800 mg, and most conveniently 20 to 200 mg, calculated as the free base.
The present invention provides a process for preparing compounds of formula (I) and pharmaceutically acceptable derivatives thereof.
Compounds of formula (I) and pharmaceutically acceptable derivatives thereof may be prepared by any method known in the art for the preparation of compounds of analogous structure.
Suitable methods for the preparation of compounds of formula (I) and pharmaceutically acceptable derivatives thereof are described below and which form a further aspect of the invention. In the formulae that follow, R1 to R4 are as defined in formula (I) above unless otherwise stated. According to a first process (A), compounds of formula (I) may be prepared by interconversion, utilising other compounds of formula (I) as precursors.
Thus, compounds of formula (I) wherein X is S may be prepared from the corresponding compound of formula (I) wherein X is O, by treatment with a thiation agent, preferably Lawessons reagent. Conveniently, the reaction is effected in the presence of a solvent or solvents, such as a halogenated hydrocarbon (e.g. dichloromethane) and/or toluene and at elevated temperature, for example 100xc2x0 C.
According to another process (B), compounds of formula (I), where R4 is xe2x80x94CONH2, may be prepared from a compound of formula (II) 
by hydrolysis under suitable reaction conditions and according to conventional procedures, eg. using sulphuric acid.
According to another process (C), compounds of formula (I) where X is O may be prepared under suitable reaction conditions by reacting a compound of formula (III) 
or a protected derivative thereof, where Hal (D) represents a halogen atom, suitably bromine, with a palladium catalyst, preferably palladium (II) acetate, a ferrocene, preferably bis(diphenylphosphino)ferrocene and an amine, in the presence of carbon monoxide. The reaction is carried out in a solvent, such as dimethylformamide and at elevated temperature, for example between 65xc2x0 C. and 125xc2x0 C.
Compounds of formula (II) may be prepared by reacting compounds of formula (III) or a protected derivative thereof, where Hal (D) represents a halogen atom, suitably bromine, with a cyanating agent preferably with a mixture of sodium cyanide and copper (I) cyanide. The reaction is carried out in a solvent, such as dimethylformamide and at elevated temperature, for example 130xc2x0 C.
Compounds of formula (III) may be prepared by reacting compounds of formula (IV) 
or a protected derivative thereof with a suitable halogenating agent, for example N-bromosuccinimide. The reaction is conveniently carried out in a suitable solvent, such as dimethylsulfoxide and below room temperature, for example 15xc2x0 C.
Compounds of formula (IV) where R2 represents NH2 may be prepared by cyclisation and oxidation of a compound of formula (V) 
or a salt thereof according to conventional procedures, for example by neutralising a salt of a compound of formula (V), e.g. with lithium hydroxide in a suitable solvent such as an alcohol, e.g. methanol, under which conditions spontaneous oxidation to a compound of formula (IV) occurs.
Compounds of formula (V) may be prepared by reacting compounds of formula (VI) R1C(O)H with compounds of formula (VII) R3 
or a salt thereof, in the presence of a cyanide source, for example potassium cyanide. Compounds of formula (VI), where R1 is trihalo-substituted phenyl, for example 2,3,5-trichlorobenzaldehyde, are known and may be prepared according to the methods described in WO95/07877. Compounds where R1 represents alternative values are either known or may be prepared according to methods known for the preparation of known compounds.
Compounds of formula (VII), for example aminoacetamidine, may be prepared according to known procedures, for example, those described in Chem. Berichte, 89, 1185 (1956).
Compounds of formula (IV) may also be prepared from compounds of formula (VII) 
or a protected derivative thereof where Hal (B) represents a halogen atom, suitably chloride. For example, Hal(B) may be converted to xe2x80x94NRbRc by reaction with an appropriate amine in a solvent, such as ethanol and at elevated temperature, for example 180xc2x0 C.
A compound of formula (VIII) may suitably be prepared from a compound of formula (IX) 
or a protected derivative thereof by reaction with a compound of formula (X) R1B(OH)2 in the presence of a palladium catalyst, preferably tetrakis(triphenylphospine)palladium(0). Examples of compounds of formula (X) R1B(OH)2 include 2,3,5-trichlorobenzeneboronic acid, 2,3-dichlorobenzeneboronic acid and 2,5-dichlorobenzeneboronic acid. Appropriately, Hal(A) in above formula (IX) is more reactive than Hal(B), and suitably Hal(A) is selected from bromide and iodide, whereas Hal(B) is aptly chloride. Compounds of formula (X) are either commercially available or can suitably be prepared from commercially available benzene analogues e.g. 1-bromo-2,3-dichlorobenzene or 2-bromo-4,6-dichloroaniline as described hereinafter in greater detail in the accompanying Examples.
A compound of formula (IX) can be suitably prepared by further halogenating a compound of formula (XI) 
or a protected derivative thereof for example by reaction with a halogenating agent, such as N-bromosuccinimide, with stirring at below room temperature, for example between xe2x88x925xc2x0 C. and 0xc2x0 C., for several hours.
A compound of formula (XI) can be prepared from a di-halo compound of formula (XII) 
by reaction with R2H, where Hal(B) and Hal(C) may be the same or different halogen substituents. Aptly both Hal(B) and Hal(C) are chloride. Compounds of formula (XII) are commercially available. The reaction is carried out at elevated temperature, for example 150xc2x0 C.
Certain intermediates described above are novel compounds, and it is to be understood that all novel intermediates herein form further aspects of the present invention.
Conveniently, compounds of the invention are isolated following work-up in the form of the free base. Pharmaceutically acceptable acid addition salts of the compounds of the invention may be prepared using conventional means.
Solvates (e.g. hydrates) of a compound of the invention may be formed during the work-up procedure of one of the aforementioned process steps.